Metabolic interactions between connective tissue cells and their surrounding matrix, finely regulated in the course of normal growth and tissue remodelling, are distorted in several skeletal disorders. Osteoarthritis and rheumatoid arthritis will serve as convenient models. Pathophysiologic mechanisms in both likely involve degradative matrix depletion plus inappropriate or inadequate repair. Collagen and proteoglycan synthesis in vitro will be examined by radioactive labelling and chemical isolation methods using normal and diseased human cartilage. The biosynthetic response to enzyme-induced matrix depletion will be examined in animal cartilage preparations. Chondrocytes in monolayer or suspension culture will be used to evaluate the role of extracellular environment (cell density, stage of aggregation, oxygen tension, nutritional factors, polyanions) in determining cellular metabolic patterns. The apparent change in type of collagen synthesis when chondrocytes are freed from their surrounding matrix provides a useful model of osteoarthritis, in which a similar pattern is thought to represent an inappropriate attempt at repair. Cloning experiments will be made in order to resolve the question of cohort selection from a microheterogeneous cell pool vs. phenotypic alteration of pre-existing cells.